There are two categories of factors capable to induce the damage of cells and tissues - endogenous and exogenous. Endogenous damaging factors include immunopathological reactions, and some neurological and genetical disorders. Exogenous factors can be divided into:
Immunopathological reactions may be also triggered by exogenous antigens. Genetically caused alterations leading to inflammation are manifested by destruction of membrane structures, by derangement of transport mechanisms, or by defective activity of some enzymes and mediators. Cell damage also occurs during ageing. It is very complicated process in which genetic, metabolic, immunologic, neurological and other factors are involed. In ageing cells, probably metabolic intermediates such as different free radicals, aldehydes, ketones, and their reaction products, or on the contrary non-degradable compounds are accumulated. This results in a serious defect in the integrity and physiological homeostasis of cells and tissue.
It seems that aging cells are losing their multiplication capacity at a particular generation. For instance, cultivated fibroblasts lose their ability to multiply between 40 and 60 generations. The cell aging may result as a tissue atrophy. In other cases, hypertrophy or hypoplasia is the compensatory mechanism for this situation. The altered cellular activities may lead to metaplasia, dysplasia, or neoplasia because aging cells are more susceptible to destruction of their DNA, RNA and vital proteins.
Extremly low temperature is able to form crystals inside the cell. Mild decrease in temperature causes paralysis of vasomotors and an increase in permeability of vessels. Blood viscosity rises proportionally with the lowering temperature and cells are destroyed by hypoxia. Low temperature acting for a longer time provokes the destruction of myelin in exposed area. Microthrombi are produced in vessels and they are the cause of gangrene.
High temperature increases the permeability of cell membranes. Very high temperature is responsible for the coagulation of vessels and denaturation of vital biopolymers, especially proteins.
According to the dose and the way of exposition ionizing irradiation may primarily damage haematopoietic, gastrointestinal or neural tissues. Whole-body irradiation produces nonspecific immunosupression which is the cause of increased sensitivity to infection. The infection is developed mainly due to leukopenia and the loss of physical integrity of mucosal membranes especially in the gastrointestinal tract. Whole-body irradiation eliminates most of the mature lymphocytes of the immune system while preserving the more radiation-resistant elements such as the thymic epithelium. Ionizing radiation is also used for the treatment of patient with cancer and sometimes in the form of local graft irradiation. An alternative form of radiation therapy is total lymphoid irradiation e.g. for the treatment of Hodgkin's disease. Lethally irradiated persons can be given immature bone marrow cells to reconstitute the immune systems.
On the cell level, irradiation destroy important biopolymers (DNA, proteins) and biological membranes. At first, the degenerative changes of nucleus and chromosomal aberrations can be seen. The increased membrane permeability and activation of hydrolytic lysosomal enzymes disrupt cell structures and compartments. Irreversible damage of irradiated cells causes their complete destruction, necrosis.
Some chemicals, namely caustic agents and mineral acids are able to damage tissues directly, other such as heavy metals, poisons and venoms mainly derange important enzymatic reactions. Metabolic homeostasis of cells and tissues is also disturbed by the action of genotoxic and proteotoxic agents. To the often observed defects belong: destruction of cell membranes, decrease of intracellular pH, release of lysosomal enzymes and changes similar as in hypoxia (decrease of oxidative phosphorylation). Lysosomal enzymes and free radicals derived from oxygen (reactive oxygen intermediates - ROI) or from nitrogen (reactive nitrogen intermediates - RNI) have an essential role in the damage of cell structures especially during the injuring inflammation. These substances may be also activated by the action of many amphiphilic detergents that are components of different cleaning and washing preparations and tooth pastes. They are dangerous if they reach inside the body in the inappropriate amount or in the inappropriate way.
The oxygen deficiency is manifested in 3--5 minutes. In mitochondria, oxidative phosphorylation is very quickly impaired and insufficient production of ATP appears. Deficiency of ATP activates anaerobic metabolism in which ATP is formed from glycogen. But the reserves of glycogen are again quickly depleted. Because of persistent ATP insufficiency the sodium-potassium pump loses its operating capacity. This leads to the intracellular accumulation of sodium and the leakage of potassium from cells. Accumulation of sodium induces the transfer of ions and water into cell. It is the reason of endoplasmic reticulum dilatation. The dilatation provides complete damage to ribosomes and blocks proteosynthesis.
If the hypoxia continues, the whole cell is overfilled with water, sodium, and chlorides. This state is still reversible, after the renewing of oxygen transport, the cell should recover. In the others cases, vacuoles in the cytoplasm and the damage of mitochondrial membrane appear. Now, it is the irreversible process. Because of the membrane damage, the extracellular calcium may enter the cell and accumulate in mitochondria. The production of ATP is completely terminated that is thought to be the real death of cell. The cell or tissue death is performed as necrosis.
Cell damage may be also caused by different gasses, especially by nitrogen oxides, sulphur dioxide, carbon monoxide, formaldehyde, chlorine, etc. Carbon monoxide is bound by hemoglobin with 300times higher affinity than oxygen. Therefore the exposure to CO develops the secondary oxygen deficiency due to the termination of oxygen transport to cells.
Infections are often involved in cell damage. Virulence
of microorganisms and the induction of inflammation depend on
their ability to replicate in human or animal body and to destroy
cellular structures. During growth and multiplication,
microorganisms can produce and release different exotoxins which
are potent injuring agents. Other microorganisms, after
destruction or lysis, release from phospholipid and
lipopolysaccharide envelops toxins known as endotoxins. The term
'' endotoxin'' is generally used to refer to the thermostable
polysaccharide toxin, firmly bound to the bacterial cell, in
contrast to the thermolabile protein '' exotoxin'', secreted
into the external environment.
Endotoxin (lipolysaccharide,
LPS) is responsible for many pathophysiological symptoms observed
during gram-negative bacterial infections. They include
pyrogenicity (the ability to cause an increase in body
temperature), changes in the number of circulating leukocytes
(leukocytopenia, leukocytosis), complement activation, activation
of macrophages, aggregation of platelets, increase of capillary
permeability and others. In addition, LPS induces an immune
response. Administration or release of a higher dose of endotoxin
may produce lethal shock. All these biological activities are
mediated through the endogenous mediator -- tumor necrosis
factor-
(TNF-
).
Viruses do not produce exotoxins or endotoxins. They are typical intracellular parasites and use cells for their own replication. During this, damage of cell structures leading to the death of cell is observed. In addition viruses may be responsible for the tumorous transformation of cells.
During the immune responses, the cells may be damaged by effector cells and molecules participating in immune mechanisms. From this point of view they are thought to be the immunopathological responses. They include:
It follows that cell damage following the inflammatory reaction may be useful or harmful. The useful activities include:
To the harmful inflammatory reactions belong autoimmune and other immunopathological processes.
